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2-triazolyl thiochromone compound and synthesis method thereof, and applications of 2-triazolyl thiochromone compound in preparation of antifungal drugs

A compound, the technology of thiochromone, which is applied in the application field of preparing antifungal drugs, can solve the problems of limited development prospects, strong cytotoxicity, and narrow antifungal spectrum

Active Publication Date: 2017-09-12
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Antifungal antibiotics, mainly polyene antibiotics, are drugs that act on ergosterol on fungal membranes. In recent years, although various new antifungal antibiotics have been reported in various countries, some of them are only resistant to plant fungi, while most of them are resistant to animal fungi. The antifungal spectrum of fungal antibiotics is too narrow, or the activity in the body is weak, or the cytotoxicity is strong, etc., and there are not many development prospects
Azole antifungal drugs are ergosterol biosynthesis inhibitors, which are the most widely used drugs in clinical practice, including imidazoles and triazoles. The existing azole antifungal drugs generally have a relatively wide antifungal spectrum, but There are still differences between each drug, and there are also certain toxic side effects and drug resistance
And other antifungal drugs are also accompanied by problems such as broad-spectrum antifungal and narrow antifungal, certain drug resistance and toxicity.

Method used

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  • 2-triazolyl thiochromone compound and synthesis method thereof, and applications of 2-triazolyl thiochromone compound in preparation of antifungal drugs
  • 2-triazolyl thiochromone compound and synthesis method thereof, and applications of 2-triazolyl thiochromone compound in preparation of antifungal drugs
  • 2-triazolyl thiochromone compound and synthesis method thereof, and applications of 2-triazolyl thiochromone compound in preparation of antifungal drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1, the synthetic preparation reaction formula of formula III1 is as follows:

[0051]

[0052] Follow the steps to prepare:

[0053] Add 22.4mmol of methyl 2,4-dichloro-5fluorobenzoylacetate, 30mL of DMSO, and 45mmol of NaOH into a single-necked flask, heat up to 40°C under stirring, and add CS dropwise at this temperature 2 26.3 mmol in 5 mL DMSO. After dropping, the temperature was controlled at 40°C and the reaction was stirred. After the reaction is complete, cool to room temperature, add 26.3 mmol of iodoethane in 10 mL of DMSO solution dropwise, after the drop is complete, react at room temperature until the reaction is complete, stir the reaction solution and pour it into 50 mL of ice water, a large amount of solids are precipitated, collect the solids by filtration, and put them in ethanol After recrystallization, 16.8 mmol of methyl 2-ethylthio-6-fluoro-7-chlorothiochromone-3-carboxylate, a product of formula (III1), was obtained, with a yield ...

Embodiment 2- Embodiment 20

[0055] Embodiment 2-embodiment 20: the preparation of formula (III) thiochromone compound

[0056] With (IV) compound as raw material, prepare product formula (III) compound (target product is each compound of formula (III2)~(III15) in table 1), preparation step is the same as embodiment 1, and reaction formula is as follows:

[0057]

[0058] In Example 2 to Example 15, the selection of each group of the product formula (III) thiochromones and the preparation reagents and detection data are listed in Table 1.

[0059] Table 1

[0060]

[0061]

[0062]

[0063]

Embodiment 16

[0064] Embodiment 16: Synthesis and preparation of formula III16 The reaction formula is as follows:

[0065]

[0066] Prepare as follows:

[0067] Into a 100mL single-necked flask, add 10mmol of 2-ethylthio-6-fluoro-7-chlorothiochromone-3-carboxylate, 20mL of acetic acid in sequence, heat to 65°C, and dropwise add 30% H 2 o 2 12mmol was stirred and reacted for 6 hours, and sodium sulfite was added to extract it, and the solvent acetic acid was distilled off under reduced pressure, then extracted with 50mL dichloromethane and 50mL water, the dichloromethane layer was taken, washed twice with water (50mL×2), the organic layer was recovered, and the The product of formula (III16) was distilled to obtain 9.5 mmol of methyl 2-ethanethionyl-6-fluoro-7-chlorothiochromone-3-carboxylate, with a yield of 95%.

[0068] 1 HNMR (DMSO-d 6 ): 1.28(t, 3H), 3.06-3.18(m, 1H), 3.31-3.43(m, 1H), 3.87(s, 3H), 8.16(d, 1H), 8.60(d, 1H).

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Abstract

The present invention relates to a 2-triazolyl thiochromone compound (formula I), which has the following structure, wherein R1 is a five-membered triazolyl ring substituted by hydrogen or C1-C3 alkyl, R2 is hydroxyl, C1-C6 hydrocarbyloxy, C1-C6 hydrocarbylamino, C1-C6 hydrocarbonyl, phenyl, phenyl substituted by one or a plurality of C1-C6 hydrocarbyloxy, phenoxy and phenoxy substituted by one or a plurality of C1-C6 hydrocarbyloxy, R3, R4 and R6 are respectively and independently selected from hydrogen, fluorine, chlorine, bromine and iodine, and R5 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 hydrocarbyloxy, C1-C6 hydrocarbylamino, phenoxy, and phenoxy substituted by one or a plurality of C1-C6 hydrocarbonyl or hydrocarbyloxy. According to the present invention, the compound can be used for preparing antifungal drugs, provides strong antibacterial activity on common pathogenic fungi and deep fungal infections, and has advantages of low toxicity, good stability, and wide anti-fungal spectrum. The formula I is defined in the specification.

Description

technical field [0001] The invention relates to an antifungal 2-azole thiochromone compound, a synthesis method of the compound and its application in the preparation of antifungal drugs. Background technique [0002] Fungi exist in large quantities in nature, and many fungi can cause various diseases of animals and plants, which not only endanger the growth of animals and plants, but more importantly, affect human health and threaten the safety of human life. [0003] In recent years, due to the rapid increase in the incidence of immunocompromised populations, including malignant tumors, malignant blood diseases, AIDS, SARS, diabetes, and severe burns, as well as the widespread use of broad-spectrum antibiotics and immunosuppressants, catheters, intubations, and organ transplants, etc. With the development of new technologies, the incidence of fungal infections of opportunistic deep organs is getting higher and higher, and it is also getting more and more serious. Data sho...

Claims

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Application Information

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IPC IPC(8): C07D409/04A61K31/4178A61K31/4196A01N43/50A01N43/653A61P31/10A01P3/00
CPCA01N43/50A01N43/653C07D409/04
Inventor 肖涛冯议胡彪陈国策
Owner NANJING UNIV OF TECH
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